Inspiratory synthesis of nitric oxide

ABSTRACT

A system for generating nitric oxide can include an apparatus positioned in a trachea of a mammal, the apparatus in-eluding a respiration sensor for collecting information related to one or more triggering events associated with the trachea, an oxygen sensor for collecting information related to a concentration of oxygen in a gas, and one or more pairs of electrodes for initiating a series of electric arcs to generate nitric oxide, and the system for generating nitric oxide can also include a controller for determining one or more control parameters based on the information collected by the respiration sensor and the oxygen sensor, wherein the series of electric arcs is initiated based on the control parameters determined by the controller.

CLAIM OF PRIORITY

This application claims the benefit of U.S. Patent Application Ser. No.61/789,161 and U.S. Patent Application Ser. No. 61/792,473, filed onMar. 15, 2013, the entire contents of which are hereby incorporated byreference.

TECHNICAL FIELD

This invention related to synthesis of nitric oxide triggered byinspiratory flow.

BACKGROUND

Nitric oxide (NO) is crucial to many biological systems, and is known tomediate the control of blood pressure, help the immune system killinvading parasites that enter cells, inhibit division of cancer cells,transmit signals between brain cells, and contribute to the large scaledeath of brain cells that can debilitate people with strokes orHuntington's disease. Nitric oxide also mediates relaxation of smoothmuscle present, for example, in the walls of the blood vessels, bronchi,gastrointestinal tract, and urogenital tract. Administration of nitricoxide gas to the lung by inhalation has been shown to produce localizedsmooth muscle relaxation to treat bronchial constriction and pulmonaryhypertension, pneumonia, etc. in adults and children without systemicside effects.

Inhaled nitric oxide is a potent local pulmonary vasodilator andbronchodilator that improves the matching of ventilation with perfusion,thereby increasing the injured lungs oxygen transport efficiency andraising the arterial oxygen tension. Nitric oxide combines a rapid onsetof action occurring within seconds with the absence of systemicvasodilatory effects. Once inhaled, it diffuses through the pulmonaryvasculature into the bloodstream, where it is rapidly inactivated bycombination with hemoglobin. Therefore, the bronchodilator effects ofinhaled nitric oxide are limited to the airway and the vasodilatoryeffects of inhaled nitric oxide are limited to the pulmonaryvasculature. The ability of nitric oxide to dilate pulmonary vesselsselectively provides therapeutic advantages in the treatment of acuteand chronic pulmonary hypertension.

U.S. Pat. No. 5,396,882 to Zapol, which is incorporated by referenceherein, describes electric generation of nitric oxide (NO) from air atambient pressure for medical purposes. As described in U.S. Pat. No.5,396,882, an air input port of the system is used for continuouslyintroducing air into the electric arc chamber. Unwanted by-productsformed during the production of NO (e.g., nitrogen dioxide (NO₂) andozone (O₃)) are absorbed, for example, by a scavenger or catalyticconverter before the electrically generated NO is used for medicalpurposes.

NO oxidizes in an oxygen-containing atmosphere to form NO₂. NO₂ is atoxic by-product which forms nitric acid when dissolved in airwaysecretions or cells. Generating NO with low levels of NO₂ is oftendesirable.

SUMMARY

In some aspects, a method includes collecting information related to oneor more triggering events associated with a respiratory system. Themethod also includes determining one or more control parameters based onthe collected information. The method also includes initiating a seriesof electric arcs to generate nitric oxide based on the determinedcontrol parameters.

Embodiments can include one or more of the following.

The triggering event can be a reduction of temperature due to aninspiration of gas.

The triggering event can be a flow of gas.

The information related to one or more triggering events can include oneor more of an onset time of an inspiration, a tidal volume of aninspiration, a temperature of an inspired gas, and a concentration ofoxygen in a reactant gas.

The series of electric arcs can be produced when the triggering eventoccurs.

The series of electric arcs can be produced a pre-defined amount of timebefore the triggering event occurs.

A pulse train can initiate the series of electric arcs, and the pulsetrain can include pulse groups having pulses with different pulsewidths.

The pulse width of initial pulses in one of the pulse groups can bewider than other pulses in the pulse group.

The series of electric arcs can generate a reduced level of nitrogendioxide or ozone.

The reduced level of nitrogen dioxide can have a concentration that isless than 20%, 10%, 6%, or 5% of a concentration of the generated nitricoxide.

The respiratory system can include a trachea.

The respiratory system can include one or both of a tracheostomy tubeand an endotracheal tube.

The respiratory system can include a patient wearable mask.

In some additional aspects, an apparatus includes a respiration sensorfor collecting information related to one or more triggering eventsassociated with a respiratory system. The apparatus also includes anoxygen sensor for collecting information related to a concentration ofoxygen in a gas. The apparatus also includes a controller fordetermining one or more control parameters based on the collectedinformation. The apparatus also includes electrodes for initiating aseries of electric arcs to generate nitric oxide based on the determinedcontrol parameters.

Embodiments can include one or more of the following.

The triggering event can be a reduction of temperature due to aninspiration of gas.

The triggering event can be a flow of gas past the respiration sensor.

The information related to one or more triggering events can include oneor more of an onset time of an inspiration, a tidal volume of aninspiration, a temperature of an inspired gas, and a concentration ofoxygen in a reactant gas.

The electrodes can produce the series of electric arcs when thetriggering event occurs.

The electrodes can produce the series of electric arcs a pre-definedamount of time before the triggering event occurs.

A pulse train can initiate the series of electric arcs, and the pulsetrain can include pulse groups having pulses with different pulsewidths.

The pulse width of initial pulses in one of the pulse groups can bewider than other pulses in the pulse group.

The series of electric arcs can generate a reduced level of nitrogendioxide or ozone.

The reduced level of nitrogen dioxide can have a concentration that isless than 20%, 10%, 6%, or 5% of a concentration of the generated nitricoxide.

The respiratory system can include a trachea.

The respiratory system can include one or both of a tracheostomy tubeand an endotracheal tube.

The respiratory system can include a patient wearable mask.

The patient wearable mask can include one or more valves for separatingan inspiratory gas flow from an expiratory gas flow.

The sensor or the electrodes can be configured to be positioned in atrachea.

The electrodes can include a noble metal.

The electrodes can include iridium.

The electrodes can include nickel.

In some additional aspects, a system for generating nitric oxideincludes an apparatus positioned in a trachea of a mammal. The apparatusincludes a respiration sensor for collecting information related to oneor more triggering events associated with the trachea. The apparatusalso includes an oxygen sensor for collecting information related to aconcentration of oxygen in a gas. One or more pairs of electrodes areincluded in the apparatus for initiating a series of electric arcs togenerate nitric oxide. The system for generating nitric oxide alsoincludes a controller for determining one or more control parametersbased on the information collected by the respiration sensor and theoxygen sensor, wherein the series of electric arcs is initiated based onthe control parameters determined by the controller.

Embodiments can include one or more of the following.

The triggering event can be a reduction of temperature due to aninspiration of gas.

The triggering event can be a flow of gas past the respiration sensor.

The information related to one or more triggering events can include oneor more of an onset time of an inspiration, a tidal volume of aninspiration, a temperature of an inspired gas, and a concentration ofoxygen in a reactant gas.

The electrodes can produce the series of electric arcs when thetriggering event occurs.

The electrodes can produce the series of electric arcs a pre-definedamount of time before the triggering event occurs.

A pulse train can initiate the series of electric arcs, and the pulsetrain can include pulse groups having pulses with different pulsewidths.

The pulse width of initial pulses in one of the pulse groups can bewider than other pulses in the pulse group.

The series of electric arcs can generate a reduced level of nitrogendioxide or ozone.

The reduced level of nitrogen dioxide can have a concentration that isless than 20%, 10%, 6%, or 5% of a concentration of the generated nitricoxide.

The electrodes can include a noble metal.

The electrodes can include iridium.

The electrodes can include nickel.

In some additional aspects, an apparatus implantable in theintercartilaginous rings in the neck includes a respiration sensor forcollecting information related to one or more triggering eventsassociated with a respiratory system. The apparatus also includes anoxygen sensor for collecting information related to a concentration ofoxygen in a gas. The apparatus also includes a controller fordetermining one or more control parameters based on the collectedinformation. One or more pairs of electrodes are included in theapparatus and reside inside a spark chamber, the electrodes forinitiating a series of electric arcs to generate nitric oxide based onthe determined control parameters, wherein the spark chamber isseparated from an external environment by a membrane that is permeableto nitric oxide and impermeable to nitrogen dioxide and ozone.

Embodiments can include one or more of the following.

The apparatus can also include a sweeping device for removing mucus fromthe membrane.

In some additional aspects, an apparatus implantable in the trachea of amammal using the Seldinger technique includes a respiration sensor forcollecting information related to one or more triggering eventsassociated with a respiratory system. The apparatus also includes anoxygen sensor for collecting information related to a concentration ofoxygen in a gas. The apparatus also includes a controller fordetermining one or more control parameters based on the collectedinformation. One or more pairs of electrodes are included in theapparatus for initiating a series of electric arcs to generate nitricoxide based on the determined control parameters.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a block diagram of a system for producing NO.

FIG. 2A shows an example of an NO generator.

FIG. 2B shows an example of an NO generator.

FIG. 2C shows an example of an NO generator.

FIG. 2D shows an example of an NO generator.

FIG. 3 depicts a representation of a pulse train and a pulse group.

FIG. 4 is a circuit diagram of an example of a portion of a respirationsensor.

FIG. 5 depicts an example of a voltage time series from a respirationsensor.

FIG. 6A shows average current and voltage as a function of sparks persecond.

FIG. 6B shows average power as a function of sparks per second.

FIGS. 7A-B show tracings of voltage and current during two sparks of a 1spark/second discharge.

FIG. 8 shows NO and NO₂ concentrations using various electrodematerials.

FIG. 9 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 10 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 11 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 12 shows ozone levels at various oxygen concentrations.

FIG. 13 shows ozone levels at various oxygen concentrations.

FIG. 14 shows ozone levels at various oxygen concentrations.

FIG. 15 shows ozone levels at various oxygen concentrations.

FIG. 16 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations.

FIG. 17 shows mean pulmonary artery pressure over an infusion period.

FIG. 18 shows NO and NO₂ concentrations at various FiO₂.

FIG. 19 shows mean pulmonary artery pressure at various FiO₂.

FIG. 20 shows NO and NO₂ concentrations at various FiO₂.

FIG. 21 shows mean pulmonary artery pressure at various FiO₂.

FIG. 22 shows mean pulmonary artery pressure at various tidal volumes.

FIG. 23 shows NO and NO₂ concentrations at various tidal volumes.

FIG. 24 shows a test setup for measuring NO and NO2 levels in ahypobaric chamber at various atmospheric pressures.

FIG. 25 shows NO and NO₂ levels at various atmospheric pressures.

FIG. 26 shows mean pulmonary artery pressure over an infusion period.

FIG. 27 shows mean pulmonary artery pressure while breathing NO.

FIG. 28 shows mean pulmonary artery pressure during sparking triggeredupon inspiration.

FIG. 29 shows mean pulmonary artery pressure during continuous sparking.

FIG. 30 shows a spark plug installed in a sheep's airway.

FIG. 31 shows mean pulmonary artery pressure during an infusion periodof the pulmonary vasoconstrictor U46619.

FIG. 32 shows mean pulmonary artery pressure while breathing NO.

FIG. 33 shows mean pulmonary artery pressure during sparking triggeredupon inspiration.

FIG. 34 shows a bench test setup with a sheep airway simulator.

FIG. 35 shows NO production under a constant reactant gas flow rateusing a modified mini spark plug with a circuit gap.

FIG. 36 shows a modified mini spark plug with a circuit gap.

FIG. 37 is a flowchart.

FIG. 38 illustrates an example of a computing device and a mobilecomputing device that can be used to implement the operations andtechniques described herein.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

As described herein, electrical synthesis of nitric oxide is initiatedupon (or before) inspiration to provide in-situ, on-demand production ofnitric oxide for therapeutic use. FIG. 1 shows an example of a system100 for producing NO in a respiratory system. In some examples, arespiratory system includes the trachea of a mammal, a respiratory mask,nasal prongs, a ventilator, or an anesthesia machine, to name a few. Areactant gas (e.g., air, or a 20-90% oxygen mixture in nitrogen) entersan NO generator 102, and a product gas (including NO) exits the NOgenerator 102. The NO generator 102 includes electrodes 106, arespiration sensor 108, and a controller 110. If the reactant gas is agas other than air, the NO generator 102 can include an oxygen sensor112. The oxygen sensor 112 can be an electrode configured to detect theconcentration of oxygen in the reactant gas. The electrodes 106 generatesparks in the presence of the reactant gas to produce NO 104, asdescribed herein.

In some embodiments, the NO generator 102 is portable and wearable. Forexample, FIG. 2A shows an example of an NO generator 200 for producingNO that can reside within the trachea of a mammal. The device can beplaced in the larynx with a fiber bronchoscope, and anchored to thetracheal wall. FIG. 2A depicts a cross-sectional view of a trachea 202with tracheostomy or endotracheal tube 204 positioned in the trachea202. The NO generator 200 is coupled to the tracheostomy or endotrachealtube 204. The NO generator 200 includes electrodes 206 and respirationsensor 208. In some examples, the NO generator 200 includes an oxygensensor 209. The NO generator 200 may include a controller 210 that iscoupled to the electrodes 206, the respiration sensor 208, and theoxygen sensor 209. In some examples, the controller 210 is separate fromthe NO generator 200. The NO generator 200 may include more than onerespiration sensor 208.

In some examples, the electrodes 206 can be duplicated for safetypurposes to provide a spare. The electrodes 206 can be doubled ortripled for increased power and NO production, e.g., with large tidalvolumes.

The electrodes, power feed, and sensor wires can be embedded in the wallof the tracheostomy or endotracheal tube 204. The electrodes may bepositioned within the tube, or placed in a small enclosure or well inthe wall of the tube. The enclosure can be a spark reaction chamber thatis covered by a microporous membrane to shield the electrodes from mucusor respiratory secretions. The membrane can also be a semipermeablemembrane (permselective) such as DMPS that passes NO without passingwater vapor. The membrane can be any membrane for passing NO withoutpassing NO₂. A small internal scraper can be placed over the membrane toremove adherent mucus or respiratory secretions that might preventdiffusion of the NO into the lumen. The scraper may be controlledexternally.

The controller 210 may be internal to or external from the user. Forexample, the controller 210 may be coupled to a user (e.g., an arm bandor belt) or implanted subcutaneously in the user. Electrodes 206,respiration sensor 208, and leads 212 may be embedded in the wall oftracheostomy or endotracheal tube 204 or positioned inside or affixed toan exterior of the tracheostomy or endotracheal tube 204. Leads 212 maybe insulated with an inert material. The leads 212 can be coupled to theelectrodes 206 and the respiration sensor 208. In some examples, theleads 212 can be separately placed via a needle puncture between thecartilaginous tracheal rings (Seldinger technique). Respiration sensor208 may be, for example, one or more of a pressure sensor, a temperaturesensor, a gas velocity sensor (e.g., a heated wire anemometer), a tidalvolume sensor, an abdominal or thoracic plethysmographic band(Respitrace™) or the like. In some cases, electrodes 206 and/orrespiration sensor 208 are at least partially covered by a shield 214.Shield 214 may be positioned proximate to a balloon 216 of thetracheostomy or endotracheal tube 204, designed to insulate the airwayfrom electrical shock and to keep electrodes 206 and respiration sensor208 clean.

In some cases, a sweeping device, brush, scraper, sander or othercleaning device, automated or not, is coupled to shield 214. Shield 214may also include a filter, e.g., a microporous membrane such aspolytetrafluoroethylene, or a diffusible but permselective membrane suchas PDMB, or polymethylpentene (PMP), so that by-products generated atelectrodes 206 (such as NO₂ and O₃) do not pass into the airway. Thefilter or membrane may also keep particulate matter or vapor in theairway such as humidity and mucus from contacting the electrodes 206 andrespiration sensor 208.

FIG. 2B shows an example of an alternative arrangement for the NOgenerator 200 coupled to the tracheostomy or endotracheal tube 204. Inthis example, the shield 214 includes a permselective membrane 218. Thearea where the electrodes 206 reside (e.g., inside the NO generator 200)is referred to as a spark chamber. The permselective membrane 218 can beapproximately 10-50 microns thick, and may be affixed to a support mesh.The permselective membrane 218 can allow NO to pass from the NOgenerator 200 (e.g., the spark chamber) to the airway while preventingNO₂ and O₃ from passing from the NO generator 200 (e.g., the sparkchamber) to the airway. The permselective membrane 218 can also preventwater vapor from passing from the airway to the NO generator 200. Insome examples, the permselective membrane 218 can be a microporousmembrane. In this example, the respiration sensor 208 resides in thetracheostomy or endotracheal tube 204. However, the respiration sensor208 can also reside in the NO generator 200, as described with referenceto FIG. 2A. In some examples, a sweeping device is coupled to the NOgenerator 200. The sweeping device is configured to remove mucus fromthe permselective membrane 218. The sweeping device may be automated.

FIG. 2C shows an example of an NO generator 220 for producing NO that isattached to a mask 222 that can be worn by a patient. Portions of the NOgenerator 220 can be placed within a nasal cavity, for example in thevestibule behind the naris, as in the NO generator 200 of FIG. 2A. Themask 222 can be part of a respiratory system. The mask 222 is configuredto be positioned over a user's face, with electrodes 228 and respirationsensor 230 coupled to the mask 222 and positioned proximate the nasalopening of a user. In some examples, the NO generator 220 includes anoxygen sensor 234. The NO generator 220 may reside in an inspiratoryline 240 that feeds into the mask 222. The mask 222 can include one ormore valves (e.g., inspiratory valve 236 and expiratory valve 238) forseparating inspiratory gas flow from the inspiratory line 240 fromexpiratory gas flow through the expiratory line 242. A controller 232may be coupled to the NO generator 220. The controller 232 may becoupled to mask 222 or to the user. In some examples, the electrodes 228and respiration sensor 230 can be positioned in a nostril of the user.The NO generator 220 functions as described above with respect to the NOgenerator 200 of FIG. 2A. The entry to the mask 222 may have one or morevalves, an inspiration line, and an expiration line. The NO generator220 may be placed in the inspiration line.

FIG. 2D shows an example of an NO generator 250 for producing NO thatcan reside within a trachea 252. In some examples, the NO generator 250is small enough to be implanted using the Seldinger technique. The NOgenerator 250 includes electrodes 254 and a respiration sensor 256(e.g., including a thermistor). The NO generator 250 may be covered by ashield 258 to insulate the airway from electrical shock and to keep theelectrodes 254 and respiration sensor 256 clean. The NO generator mayalso include a membrane 260. The membrane 260 may be a permselectivemembrane that can allow NO to pass from the NO generator 250 to theairway while preventing NO₂ and O₃ from passing from the NO generator250 to the airway. The membrane 260 can also prevent water vapor frompassing from the airway to the NO generator 250. Wires 262 can connect apower source 264 to the NO generator 250. The wires 262 can be insulatedto protect tissue from electric shock. A controller (e.g., controller266) may be configured to communicate with the NO generator 266. Thecontroller 266 may be configured to wirelessly communicate with the NOgenerator 250. In some examples, the NO generator 250 includes thecontroller 266, and the controller 266 resides within the trachea 252.

Referring back to FIG. 2A, the NO generator 200 operates as describedherein to generate NO in the airway of a mammal based on a triggeringevent (e.g., volume and timing of gas flow, change in inspired gastemperature, or change in pressure), as detected by respiration sensor208 in some examples. The controller 210, operatively coupled torespiration sensor 208, coordinates triggering of a voltage source inthe controller 210 to deliver a series of electrical pulses toelectrodes 206, thereby generating NO in the airway of the mammal duringinspiration. The controller 210 can determine one or more controlparameters based on information that is collected from the respirationsensor 208 (e.g., information related to one or more triggering events).The controller 210 may be configured to initiate a series of sparks andto control parameters such as spark duration, spark frequency, and thelike to generate the needed amount of NO and minimal amount of NO₂. Insome examples, the voltage source in the controller 210 can be a primarycell battery, a rechargeable battery, or a piezoelectric generator.

The controller 210 can determine one or more control parameters based oninformation received from an oxygen sensor (e.g., oxygen sensor 112 ofFIG. 1). For example, the determined control parameters can be based onthe concentration of oxygen in the reactant gas.

In some examples, the respiration sensor 208 is configured to measurethe tidal volume of inspired gas. The controller 210 can determine oneor more control parameters based on the inspired gas volumemeasurements. For example, the control parameters can be based on anactual or expected volume of an inspiration.

Adult humans normally breathe from 10-20 times per minute, each breathhaving a duration of 3-6 seconds. Typically, about one half to one thirdof the breath duration is inspiration. On average, each breath has atidal volume of about 500 ml. In children, each breath typically hasless volume, but breathing occurs at a higher rate.

The expected volume of an inspiration can be calculated using previoustidal volume measurements. For example, the controller 210 may determinethat the expected tidal volume of a subsequent inspiration is going tobe the same as the tidal volume measurement for the most recentinspiration. The controller 210 can also average the tidal volumes ofseveral prior inspirations to determine the expected tidal volume of asubsequent inspiration. In some instances, mechanical ventilation isapplied via a mask to support ventilation. In those cases, theinspiratory volume and timing of inspiration can be fed to thecontroller from the ventilator device.

FIG. 3 shows a representation of a pulse train 300 that is triggered bythe controller 210. The controller 210 can determine one or more controlparameters to create a pulse train. FIG. 3 also shows zoomed in view ofone of the pulse groups 302 of the pulse train 302. Electrical pulsesare delivered to the electrodes 206, and the electrodes 206 generate aseries of sparks (sometimes referred to as electric arcs). The timing ofthe pulses (and of the resulting sparks) is controlled by the controller210, and can be optimized to produce the needed amount of NO whileproducing minimal NO₂ and O₃. Multiple sparks make up a pulse group, andmultiple pulse groups make up the pulse train. Thus, the pulse train 302initiates the series of electric arcs.

Variables B and N control the overall energy that is created by theelectrodes 206. Variable N sets the number of sparks per pulse group,and variable B sets the number of pulse groups per second. The valuesfor B and N influence the amount of NO, NO₂, and O₃ that is created. Thevalues for B and N also influence how much heat is produced by theelectrodes 206. Larger values of either B or N create more NO and causethe electrodes 206 to produce more heat.

Variables E, F, H, and P control the timing of the sparks produced ineach pulse group. Variable H is the high time of a pulse (e.g., theamount of time the voltage source of the controller 210 is activated foreach electrical pulse). The high time is sometimes referred to as thepulse width. P is the amount of time between pulses. Thus, P minus Hrepresents a period of time when no pulses occur (e.g., the voltagesource of the controller 210 is not active). Larger values of H andsmaller values of P result in the electrodes 206 producing more energy.When the electrodes 206 create a spark, plasma is established. Thetemperature of the plasma is proportional to the amount of energyproduced by the electrodes 206.

The chemical reactions that cause NO and NO₂ to be produced are afunction of plasma temperature. That is, higher plasma temperaturesresult in more NO and NO₂ being produced. However, the relativeproportions of the produced NO and NO₂ vary across different plasmatemperatures. In some examples, the sparks generated by the first twopulses in a pulse group establish the plasma. The first two sparks canhave a high time that is longer than the sparks produced by the rest ofthe pulses in the pulse group. The amount of time that the first twopulses are extended is represented by variables E and F, respectively.Sparks generated by pulses beyond the first two pulses require lessenergy to maintain the plasma, so the high time of subsequent pulses(represented by variable H) can be shorter to prevent the plasmatemperature from getting too high. For instance, while a relatively highplasma temperature may result in more NO, NO₂, and O₃ being produced,the relatively high plasma temperature may not be ideal for producingthe desired proportions of NO and NO₂.

Many factors can affect the amount and proportions of NO, NO₂, and O₃that is produced. For example, the material of the electrodes 206 playsa major role in determining how much energy is needed to generate aparticular spark. Electrodes that include a noble metal may produce alow ratio of NO₂/NO. In some examples, tungsten electrodes produce arelatively high ratio of NO₂/NO, nickel electrodes produced a lowerratio of NO₂/NO, and iridium electrodes produce an even lower ratio ofNO₂/NO, as shown in FIG. 8.

Each spark that is generated creates a particular amount of NO. The NOis diluted in the volume of gas that is inspired. To ensure theconcentration of NO in the inspired gas is at an expected and sufficientlevel to produce the desired physiological effect, the controller 210receives information related to the tidal volume of inspired gas fromthe respiration sensor 208 to determine control parameters formaintaining an appropriate NO concentration.

Implementations of the controller 210 can include digital electroniccircuitry, or computer software, firmware, or hardware, including thestructures disclosed in this specification and their structuralequivalents, or combinations of one or more of them. For example, thecontroller 210 can be a microprocessor based controller (or controlsystem) as well as an electro-mechanical based controller (or controlsystem). Instructions and/or logic in the controller 210 can beimplemented as one or more computer programs, i.e., one or more modulesof computer program instructions, encoded on computer storage medium forexecution by, or to control the operation of, data processing apparatus.Alternatively or in addition, the program instructions can be encoded onan artificially generated propagated non-transitory signal, e.g., amachine-generated electrical, optical, or electromagnetic signal that isgenerated to encode information for transmission to suitable receiverapparatus for execution by a data processing apparatus.

The controller 210 can include clients and servers and/or master andslave controllers. A client and server are generally remote from eachother and typically interact through a communication network. Therelationship of client and server arises by virtue of computer programsrunning on the respective computers and having a client-serverrelationship to each other. In some aspects, the controller 210represents a main controller (e.g., master) communicably coupled throughcommunication elements (e.g., wired or wireless) with each of thecomponents of the NO generator 200.

The controller 210 may be configured to communicate with the NOgenerator 200 wirelessly (e.g., via Bluetooth). The controller 210 canalso be configured to communicate with external devices (e.g., acomputer, tablet, smart phone, or the like). The external devices canthen be used to perform functions of the controller 210 or to aid thecontroller 210 in performing functions.

In some examples, the controller 210 can disable certain components ofthe NO generator 200 during, before or after a series of sparks isgenerated. In some examples, the controller 210 can also includefeatures to: i) detect and cease unintended sparks; ii) confirm that aseries of sparks is safe before triggering the series of sparks; iii)verify that timing values are checked against back-up copies of timingvalues after every series of sparks is generated to detect timingvariable corruption; and iv) determine whether back-up copies of timingvariables are corrupt.

In some examples, the NO generator 200 can be positioned or includedwith nasal tubes, endotracheal tubes, and the like. Electrodes 206 andrespiration sensor 208 may be cleanable or replaceable. In someexamples, the electrodes 106 and sensor 208 may be removed from thetracheostomy or endotracheal tube 204 and cleaned or replaced.

Sparking upon inspiration in the NO generator 200 tags the front of theinspired gas bolus with electrically synthesized fresh NO. In someexamples, it is desirable to generate NO only at the start ofinspiration. This minimizes the amount of freshly produced NO produced,reduces environmental pollution, and effectively delivers the NO mostrapidly without dilution into terminal bronchi and alveolar gas where itcan actively dilate the pulmonary blood vessels (the alveoli and distalairways). After a brief period of time, NO begins to oxidize into NO₂which, when dissolved in water, forms nitric acid and nitrate salts. IfNO is produced long before a user is ready to inhale it, the NO can beoxidized by the time of inspiration. The nitric acid and nitrate saltscan cause damage to the components of the NO generator 200 as well as tothe airways and lung tissue.

In some examples, to augment the dose, it may be desirable to generateNO at the end of exhalation and slightly prior to the start of aninspiration. This is sometimes referred to as pre-triggering. Thecontroller 210 can initiate the series of electric arcs for apre-defined amount of time before the triggering event occurs. Suchpre-triggering may be necessary when there is a large volume of inspiredgas or when a high concentration of inhaled NO is desired. Thecontroller 210 can track the inspiratory timing and volume of inspiredgas and use prior timings to predict the timing of a subsequentinspiration. The tracked information can be used to calculate apre-defined amount of time that represents an estimate of when the nextinspiration will occur. In some examples, the controller 210 caninitiate the series of electric arcs approximately when the triggeringevent occurs (e.g., slightly before or slightly after the triggeringevent). Pre-triggering can be optimized to ultimately deliver greater NOconcentrations in the inspired gas.

The spark can be triggered at the onset of inspiration in a number ofways. In some examples, the respiration sensor 208 detects aninspiration. The respiration sensor 208 can include a high speedresponse thermistor that is located near the electrodes 206 in theairway. The respiration sensor 208 can sense a change in temperature(inspired air is often slightly cooler than expired air). Thus the coolinspiratory gas can trigger a series of sparks. That is, an inspiration,or part of an inspiration, can be a triggering event. More specifically,a reduction of temperature due to an inspiration of air can be atriggering event.

Different types of circuitry can be incorporated into the NO generator200 and its components. FIG. 4 shows a circuit diagram 400 of an exampleof a portion of a respiration sensor 208 that can be used to detect aninspiration. The respiration sensor 208 can monitor the temperature ofthe air in the airway. The respiration sensor can include a thermistor402. The resistance of the thermistor 402 increases when it is cooledand decreases when it is warmed.

In this example, the respiration sensor 208 is set up as a voltagedivider that includes the thermistor 402 and another resistor. Analternative configuration is to use a thermistor in a bridgeconfiguration with other resistors. During inspiration, room or inspiredtemperature gas is inhaled past the thermistor 402. During expiration,gas that is typically warmer than room temperature (e.g., gas that is ator near body temperature) passes the thermistor 402. That is, duringtypical operation, the thermistor 402 increases in resistance duringinspiration and decreases in resistance during expiration. The change inresistance of the thermistor 402 results in a varying voltage in themiddle node of the voltage divider. This varying voltage may be modifiedby one or more amplifiers.

The respiration sensor 208 can include a differentiator that outputs avoltage that is proportional to the varying voltage of the voltagedivider. This voltage can be sent to the controller 210 and convertedinto a digital voltage value. The controller 210 can use the digitalvoltage value to determine the start of an inspiration. Alternatively,the output of the differentiator can be modified by an amplifier andthen fed into a Schmitt trigger. The Schmitt trigger can convert thevoltage into a digital voltage value and create a hysteresis. Thehysteresis can help differentiate between small temperature decreasesseen late in an expiration period (which are to be ignored), and largertemperature decreases seen at the start of an inspiration period (whichare of interest). The digital voltage value can be sent to thecontroller 210, which can recognize the start of an inspiration.

FIG. 5 shows an example of a voltage time series 500 of a respirationsensor 208. As explained above, during inspiration, relatively coolinhaled gas passes the thermistor 402. The cool inspired gas causes theresistance of the thermistor to increases, which in turn causes thevoltage at the middle node of the voltage divider to increase, asreflected in region 502. During expiration, relatively warm gas nearcore body temperature (approximately 37 degrees Celsius) passes by thethermistor 402. The warm gas causes the resistance of the thermistor todecrease, which in turn causes the voltage at the middle node of thevoltage divider to decrease, as reflected in region 504.

In some examples, the respiration sensor 208 can be a tube contiguouswith the area near the electrodes 206 that can sense pressure.Spontaneous inspiration is triggered by a lower airway and intrathoracicpressure, whilst mechanical ventilation produces a positive airwaypressure (to inflate the lungs). Thus, pressure sensing of inspiration,whether positive (mechanical ventilation) or negative (spontaneousinspiration) could trigger the spark. In some examples, a hot wireanemometer or a pneumotachograph can sense respiratory timings andvolume.

In some examples, a circumferential chest belt containing a resistor(e.g., mercury strain gauge) or impedance sensor could sense theexpansion of the chest (or abdomen) and thereby trigger the spark toproduce NO upon the onset of inspiration. In certain cases, if thepatient is on a respirator, the mechanical respirator or ventilator cantrigger the endotracheal or tracheostomy pulse of synthesizingelectricity (because the ventilator can know the timing, tidal volume ofthe inspiration, and the inspired oxygen concentration) to produce thenecessary amount of NO by sparks timed to the onset of ventilatorinspiration.

In cases where the respiration sensor 208 does not measure temperature,the respiration sensor 208 can be configured to detect when aninspiration or expiration occurs. The respiration sensor 208 can alsodifferentiate between an inspiration and an expiration. For example, therespiration sensor 208 can detect the air flow direction of air passingby the respiration sensor 208 to determine whether the air is beinginspired or expired.

Results achieved with the NO generator 200 (and the NO generator mask220 of FIG. 2B) are described herein.

FIG. 6A is an average current and voltage chart 600 that shows theaverage current and voltage vs. sparks/second for NO generator 200. FIG.6B is an average power chart 602 that shows the average power vs.sparks/second for NO generator 200. Average current and power peakbetween 0.5 and 2 sparks/second, and average voltage dips over the samerange. FIG. 7A shows oscilloscope traces 700 for voltage (upper trace)and current (lower trace) during 2 sparks of a 1 spark/second discharge.FIG. 7B shows oscilloscope traces 702 for voltage (upper trace) andcurrent (lower trace) traces for a 1 spark/second discharge with a sparkduration (single spark) of 27 msec.

Animal Study 1

Four lambs weighing approximately 32 kg were studied. General anesthesiawas induced with 5% inhaled isoflurane(1-chloro-2,2,2-trifluoroethyldifluromethyl ether, Baxter, Deerfield,Ill.) in oxygen via a mask and then maintained with 1-4% isoflurane atan initial inspired oxygen fraction (FiO₂) of 0.40. After trachealintubation, animals were instrumented with indwelling carotid artery andpulmonary artery Swan-Ganz catheters. All hemodynamic measurements wereperformed in the anesthetized lambs. All lambs were ventilated with amechanical ventilator (model 7200, Puritan Bennett, Pleasanton, Calif.)at tidal volume 400 ml and rate 12 breaths/min.

To induce pulmonary hypertension, the potent pulmonary vasoconstrictorU46619 (Cayman Chemical, Ann Arbor, Mich.), the analog of theendoperoxide prostaglandin H₂, was infused intravenously at a rate of0.8-0.9 μg/kg/min to increase the mean pulmonary artery pressure (PAP)to 30 mmHg.

To study the pulmonary vasodilator effect of nitric oxide (NO) producedby electric discharge, either a mini spark plug or iridium spark plugwas placed in the inspiratory line of the sheep ventilator while airwaygas flow measurements were measured by software (NICO Respironics,Wallingford, Conn.) to determine inspiration, expiration, and the tidalvolume of each mechanical breath. Electrodes of the spark plug generateda series of sparks as described with reference to FIG. 3. In somestudies, sparks were produced continuously throughout the respiratorycycle (continuous sparking). In other studies, sparks were produced oneach breath commencing with inspiration, or shortly before inspirationbegan (intermittent sparking for 0.8 seconds/breath, 12-15 breaths/min).This was done to avoid wasted NO production during the expiratory phaseof respiration.

FIG. 8 shows NO and NO₂ concentrations from an NO generator (e.g., NOgenerator 102 of FIG. 1) using various electrode materials. The testconditions included the use of a ¼″ rod, an electrode gap of 2.0 mm,constant air flow at 5 L/min, and an FiO₂ of 0.21. For the tungstenelectrode, B=40 pulse groups per second, N=30 sparks per pulse group,P=100 microseconds, and H=20 microseconds. For the nickel electrodes,B=35 pulse groups per second, N=40 sparks per pulse group, H=180microseconds, and P=70 microseconds. For the iridium electrodes, B=35pulse groups per second, N=40 sparks per pulse group, H=180microseconds, and P=80 microseconds.

FIG. 9 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations from the NO generator using mini spark plug (Micro ViperZ3 with 6 mm HEX and 10-40 THRD, Rimfire, Benton City, Wash.) withcontinuous sparking.

FIG. 10 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations from the NO generator using an iridium spark plug(ACDelco 41-101, Waltham, Mass.) with continuous sparking.

FIG. 11 shows NO and NO₂ concentrations at various reactant gas oxygenconcentrations from the NO generator using iridium spark plug withintermittent sparking.

Ozone (O₃) is a powerful oxidant that has many industrial and consumerapplications related to oxidation. However, its oxidizing potential ishigh, and it is a toxic gas causing damage to mucus membranes andrespiratory tissues in animals, and also to tissues in plants. Thismakes ozone a potent respiratory hazard and pollutant near ground level.Ozone is formed from atmospheric electrical discharges, and reacts withNO to form nitric dioxide (NO₂) and O₂ or reacts with N₂ to produce NOand O₂. In some examples, ozone levels are greater with continuoussparking than with intermittent sparking, and also increase withincreasing O₂ concentrations.

FIG. 12 shows O₃ levels at various O₂ concentrations using the minispark plug and iridium spark plug with continuous sparking. In thisexample, B=60 pulse groups per second, N=50 sparks per pulse group,P=140 microseconds, H=40 microseconds, and air flow rate is 5 L/min.

FIG. 13 shows O₃ levels at various O₂ concentrations using the minispark plug and iridium spark plug with intermittent sparking triggeredon each breath commencing with inspiration, or shortly beforeinspiration began. In this example, B=60 pulse groups per second, N=50sparks per pulse group, P=140 microseconds, H=40 microseconds, and airflow rate is 5 L/min.

FIG. 14 shows O₃ levels at various O₂ concentrations using the minispark plug and iridium spark plug with continuous sparking. In thisexample, B=35 pulse groups per second, N=25 sparks per pulse group,P=240 microseconds, H=100 microseconds, and air flow rate is 5 L/min.

FIG. 15 shows O₃ levels at various O₂ concentrations using the minispark plug and iridium spark plug with intermittent sparking triggeredon each breath commencing with inspiration, or shortly beforeinspiration began. In this example, B=35 pulse groups per second, N=25sparks per pulse group, P=240 microseconds, H=100 microseconds, and airflow rate is 5 L/min.

FIG. 16 shows NO and NO2 concentrations at various reactant gas oxygenconcentrations using an oxygen concentrator. In this example, B=5 pulsegroups per second, N=25 sparks per pulse group, P=200 microseconds, H=60microseconds, and air flow rate is 5 L/min.

FIG. 17 shows mean pulmonary artery pressure (PAP) during infusion ofU46619. At baseline, before U46619 infusion was begun, the PAP was 14mmHg. Over 30 minutes of infusion, the mean PAP increased to 28 mmHg.After PAP was stable, sparks were generated at the beginning of eachinspiration for a period of four minutes. Over the four minute period,the PAP was significantly decreased to 22 mmHg. After ceasing sparkingand waiting a four minute period, mean PAP again rose to 28 mmHg. Inthis example, B=60 pulse groups per second, N=100 sparks per pulsegroup, P=140 microseconds, H=17 microseconds, and tidal volume (Vt)=400ml.

FIG. 18 shows NO and NO₂ concentrations at various FiO₂ while producingintermittent sparks triggered by inspiratory flow using an iridium sparkplug.

FIG. 19 shows mean PAP at various FiO₂ levels during U46619 infusionbefore and after producing intermittent sparks. In these examples, B=35pulse groups per second, N=25 sparks per pulse group, P=240microseconds, H=100 microseconds, and Vt=400 ml.

FIG. 20 shows NO and NO₂ concentrations at various FiO₂ levels whileproducing continuous sparks triggered upon inspiratory flow using aniridium spark plug. FIG. 21 shows PAP at various FiO₂ levels duringinfusion of U46619 before and after producing continuous sparks. Inthese examples, B=35 pulse groups per second, N=25 sparks per pulsegroup, P=240 microseconds, H=100 microseconds, and Vt=400 ml.

In some further examples, smaller breath sizes produce higher levels ofNO because of reduced dilution of spark synthesized NO. FIG. 22 showsmean PAP at various Vt (respiratory tidal volume levels) during infusionof U46619 before and after producing NO with sparks triggered byinspiratory flow using an iridium spark plug. FIG. 23 shows NO and NO₂concentrations in lambs at the various levels of tidal volumeventilation (Vt). In these examples, B=35 pulse groups per second, N=25sparks per pulse group, P=240 microseconds, H=100 microseconds, andFiO₂=0.21.

FIG. 24 shows a test setup for measuring NO and NO₂ levels in ahypobaric chamber 2400 at various atmospheric pressures. The results ofthe test are shown in FIG. 25. To create a negative pressure (e.g., ½ATA, ⅓ ATA) inside the hypobaric chamber 2400, inlet and outlet valveswere closed and a piston was translated away from the spark plug. Thespark plug was then fired for 30 seconds. In this example, B=100 pulsegroups per second, N=10 sparks per pulse group, P=140 microseconds, andH=10 microseconds. The piston was then translated toward the spark plugto bring the pressure in the hypobaric chamber 2400 back to 1 ATA. Theoutlet valve was opened, and gas samples were collected in a 3 Lrespiratory bag by further translating the piston toward the spark plug.The collected gas samples were analyzed with Sievers NOA i280immediately after collection.

Animal Study 2

A mini spark plug (Micro Viper Z3 with 6 mm HEX and 10-40 THRD, Rimfire,Benton City, Wash.) was installed in the airway of sheep #1. The minispark plug was triggered by a respiration sensor that measured thechange in inspired gas temperature upon inspiration. Electrodes of themini spark plug generated a series of sparks as described with referenceto FIG. 3.

FIG. 26 shows PAP during an infusion of U46619 for a period of time.U46619 was IV infused at a concentration of 50 μg/ml at a rate of 18ml/hour. At baseline, the mean PAP was 13 mmHg. Over 30 minutes ofinfusion, the mean PAP increased to 27-28 mmHg.

FIG. 27 shows mean PAP while the sheep is breathing NO at aconcentration of 40 ppm from a tank. The mean PAP decreased to 18 mmHGafter two minutes.

FIG. 28 shows mean PAP during sparking triggered by inspiratorybreathing (e.g., triggered by the NICO a respiration sensor uponinspiration). In this example, B=1 pulse groups per second, N=70 sparksper pulse group, P=140 microseconds, and H=40 microseconds. In vitro at200 ml/min, the NO concentration measured by chemiluminescence was 25ppm.

FIG. 29 shows mean PAP during continuous sparking. In this example, B=1pulse groups per second, N=407 sparks per pulse group, P=140microseconds, and H=40 microseconds. In vitro at 200 ml/min, the NOconcentration was 125 ppm.

A mini spark plug was installed in sheep #2's airway, as shown in FIG.30. The mini spark plug was triggered by a respiration sensor thatmeasured the change in inspired gas temperature upon inspiration.Electrodes of the mini spark plug generated a series of sparks asdescribed with reference to FIG. 3.

FIG. 31 shows mean PAP during infusion of U46619 for a period of time.U46619 was infused at 50 μg/ml at 18 ml/hour. At baseline, the mean PAPwas 12 mmHg. Over 30 minutes of infusion, the mean PAP increased to 27mmHG.

FIG. 32 shows mean PAP while the sheep is breathing NO at a fixedconcentration of 40 ppm delivered from a cylinder. The mean PAPdecreased to 15 mmHg after two minutes.

FIG. 33 shows mean PAP during sparking triggered by inspiratorybreathing (e.g., triggered by a NICO respiration sensor uponinspiration) with flow control. In this example, B=60 pulse groups persecond, N=100 sparks per pulse group, P=140 microseconds, and H=17microseconds.

Bench Test

FIG. 34 shows a bench test setup using a micro spark plug triggered byinspiration (flow controlled, NICO monitor) with a sheep airwaysimulator.

FIG. 35 shows NO production under a constant reactant gas flow rate of 1L/min using a modified mini spark plug with a circuit gap (as shown inFIG. 36) under various conditions. In this example, H was increased from10 to 17. Continuous sparking in air produced major amounts of NO (i.e.,approximately 250 ppm). The tang electrode of the mini spark plug wasremoved during modification to increase the electrode gap from 0.4 mm to1.1 mm.

Referring to FIG. 37, a flowchart 3700 represents an arrangement ofoperations of the controller (e.g., controller 210, shown in FIG. 2A).Typically, the operations are executed by a processor present in thecontroller. However, the operations may also be executed by multipleprocessors present in the controller. While typically executed by asingle controller, in some arrangements, operation execution may bedistributed among two or more controllers.

Operations include collecting 3702 information related to one or moretriggering events associated with a respiratory system. For example, therespiration sensor 208 of FIG. 2A can collect information related one ormore triggering events associated with a respiratory system. Theinformation can include the onset time of an inspiration and the tidalvolume of an inspiration (e.g., obtained from a NICO device, a hotwireanemometer, a pneumotachograph, etc.). The triggering event may be aninspiration. Operations also include determining 3704 one or morecontrol parameter based on the collected information. For example, thecontroller 210 of FIG. 2A can determine one or more control parameters.The control parameters may create a pulse train. Operations also includeinitiating 3706 a series of electric arcs to generate nitric oxide basedon the determined control parameters. For example, the electrodes 206 ofFIG. 2A can initiate a series of electric arcs to generate nitric oxidebased on the determined control parameters. The control parameters maycontrol the timings of the series of electric arcs.

FIG. 38 shows an example of example computer device 3800 and examplemobile computer device 3850, which can be used to implement theoperations and techniques described herein. For example, a portion orall of the operations of the controller 110 (shown in FIG. 1), thecontroller 210 (shown in FIG. 2A), the controller 232 (shown in FIG.2C), or the controller 266 (shown in FIG. 2D) may be executed by thecomputer device 3800 and/or the mobile computer device 3850. Computingdevice 3800 is intended to represent various forms of digital computers,including, e.g., laptops, desktops, workstations, personal digitalassistants, servers, blade servers, mainframes, and other appropriatecomputers. Computing device 3850 is intended to represent various formsof mobile devices, including, e.g., personal digital assistants, tabletcomputing devices, cellular telephones, smartphones, and other similarcomputing devices. The components shown here, their connections andrelationships, and their functions, are meant to be examples only, andare not meant to limit implementations of the techniques describedand/or claimed in this document.

Computing device 3800 includes processor 3802, memory 3804, storagedevice 3806, high-speed interface 3808 connecting to memory 3804 andhigh-speed expansion ports 3810, and low speed interface 3812 connectingto low speed bus 3814 and storage device 3806. Each of components 3802,3804, 3806, 3808, 3810, and 3812, are interconnected using variousbusses, and can be mounted on a common motherboard or in other mannersas appropriate. Processor 3802 can process instructions for executionwithin computing device 3800, including instructions stored in memory3804 or on storage device 3806 to display graphical data for a GUI on anexternal input/output device, including, e.g., display 3816 coupled tohigh speed interface 3808. In other implementations, multiple processorsand/or multiple buses can be used, as appropriate, along with multiplememories and types of memory. Also, multiple computing devices 3800 canbe connected, with each device providing portions of the necessaryoperations (e.g., as a server bank, a group of blade servers, or amulti-processor system).

Memory 3804 stores data within computing device 3800. In oneimplementation, memory 3804 is a volatile memory unit or units. Inanother implementation, memory 3804 is a non-volatile memory unit orunits. Memory 3804 also can be another form of computer-readable medium,including, e.g., a magnetic or optical disk.

Storage device 3806 is capable of providing mass storage for computingdevice 3800. In one implementation, storage device 3806 can be orcontain a computer-readable medium, including, e.g., a floppy diskdevice, a hard disk device, an optical disk device, or a tape device, aflash memory or other similar solid state memory device, or an array ofdevices, including devices in a storage area network or otherconfigurations. A computer program product can be tangibly embodied in adata carrier. The computer program product also can contain instructionsthat, when executed, perform one or more methods, including, e.g., thosedescribed above. The data carrier is a computer- or machine-readablemedium, including, e.g., memory 3804, storage device 3806, memory onprocessor 3802, and the like.

High-speed controller 3808 manages bandwidth-intensive operations forcomputing device 3800, while low speed controller 3812 manages lowerbandwidth-intensive operations. Such allocation of functions is anexample only. In one implementation, high-speed controller 3808 iscoupled to memory 3804, display 3816 (e.g., through a graphics processoror accelerator), and to high-speed expansion ports 3810, which canaccept various expansion cards (not shown). In the implementation,low-speed controller 3812 is coupled to storage device 3806 andlow-speed expansion port 3814. The low-speed expansion port, which caninclude various communication ports (e.g., USB, Bluetooth®, Ethernet,wireless Ethernet), can be coupled to one or more input/output devices,including, e.g., a keyboard, a pointing device, a scanner, or anetworking device including, e.g., a switch or router, e.g., through anetwork adapter.

Computing device 3800 can be implemented in a number of different forms,as shown in the figure. For example, it can be implemented as standardserver 3820, or multiple times in a group of such servers. It also canbe implemented as part of rack server system 3824. In addition or as analternative, it can be implemented in a personal computer including,e.g., laptop computer 3822. In some examples, components from computingdevice 3800 can be combined with other components in a mobile device(not shown), including, e.g., device 3850. Each of such devices cancontain one or more of computing device 3800, 3850, and an entire systemcan be made up of multiple computing devices 3800, 3850 communicatingwith each other.

Computing device 3850 includes processor 3852, memory 3864, aninput/output device including, e.g., display 3854, communicationinterface 3866, and transceiver 3868, among other components. Device3850 also can be provided with a storage device, including, e.g., amicrodrive or other device, to provide additional storage. Each ofcomponents 3850, 3852, 3864, 3854, 3866, and 3868, are interconnectedusing various buses, and several of the components can be mounted on acommon motherboard or in other manners as appropriate.

Processor 3852 can execute instructions within computing device 3850,including instructions stored in memory 3864. The processor can beimplemented as a chipset of chips that include separate and multipleanalog and digital processors. The processor can provide, for example,for coordination of the other components of device 3850, including,e.g., control of user interfaces, applications run by device 3850, andwireless communication by device 3850.

Processor 3852 can communicate with a user through control interface3858 and display interface 3856 coupled to display 3854. Display 3854can be, for example, a TFT LCD (Thin-Film-Transistor Liquid CrystalDisplay) or an OLED (Organic Light Emitting Diode) display, or otherappropriate display technology. Display interface 3856 can compriseappropriate circuitry for driving display 3854 to present graphical andother data to a user. Control interface 3858 can receive commands from auser and convert them for submission to processor 3852. In addition,external interface 3862 can communicate with processor 3842, so as toenable near area communication of device 3850 with other devices.External interface 3862 can provide, for example, for wiredcommunication in some implementations, or for wireless communication inother implementations, and multiple interfaces also can be used.

Memory 3864 stores data within computing device 3850. Memory 3864 can beimplemented as one or more of a computer-readable medium or media, avolatile memory unit or units, or a non-volatile memory unit or units.Expansion memory 3874 also can be provided and connected to device 3850through expansion interface 3872, which can include, for example, a SIMM(Single In Line Memory Module) card interface. Such expansion memory3874 can provide extra storage space for device 3850, or also can storeapplications or other data for device 3850. Specifically, expansionmemory 3874 can include instructions to carry out or supplement theprocesses described above, and can include secure data also. Thus, forexample, expansion memory 3874 can be provided as a security module fordevice 3850, and can be programmed with instructions that permit secureuse of device 3850. In addition, secure applications can be providedthrough the SIMM cards, along with additional data, including, e.g.,placing identifying data on the SIMM card in a secure, non-modifiablemanner.

The memory can include, for example, flash memory and/or NVRAM memory,as discussed below. In one implementation, a computer program product istangibly embodied in a data carrier. The computer program productcontains instructions that, when executed, perform one or more methods,including, e.g., those described above. The data carrier is a computer-or machine-readable medium, including, e.g., memory 3864, expansionmemory 3874, and/or memory on processor 3852, which can be received, forexample, over transceiver 3868 or external interface 3862.

Device 3850 can communicate wirelessly through communication interface3866, which can include digital signal processing circuitry wherenecessary. Communication interface 3866 can provide for communicationsunder various modes or protocols, including, e.g., GSM voice calls, SMS,EMS, or MMS messaging, CDMA, TDMA, PDC, WCDMA, CDMA2000, or GPRS, amongothers. Such communication can occur, for example, throughradio-frequency transceiver 3868. In addition, short-range communicationcan occur, including, e.g., using a Bluetooth®, WiFi, or other suchtransceiver (not shown). In addition, GPS (Global Positioning System)receiver module 3870 can provide additional navigation- andlocation-related wireless data to device 3850, which can be used asappropriate by applications running on device 3850. Sensors and modulessuch as cameras, microphones, compasses, accelerators (for orientationsensing), etc. maybe included in the device.

Device 3850 also can communicate audibly using audio codec 3860, whichcan receive spoken data from a user and convert it to usable digitaldata. Audio codec 3860 can likewise generate audible sound for a user,including, e.g., through a speaker, e.g., in a handset of device 3850.Such sound can include sound from voice telephone calls, can includerecorded sound (e.g., voice messages, music files, and the like) andalso can include sound generated by applications operating on device3850.

Computing device 3850 can be implemented in a number of different forms,as shown in the figure. For example, it can be implemented as cellulartelephone 3880. It also can be implemented as part of smartphone 3882,personal digital assistant, or other similar mobile device.

Various implementations of the systems and techniques described here canbe realized in digital electronic circuitry, integrated circuitry,specially designed ASICs (application specific integrated circuits),computer hardware, firmware, software, and/or combinations thereof.These various implementations can include implementation in one or morecomputer programs that are executable and/or interpretable on aprogrammable system including at least one programmable processor, whichcan be special or general purpose, coupled to receive data andinstructions from, and to transmit data and instructions to, a storagesystem, at least one input device, and at least one output device.

These computer programs (also known as programs, software, softwareapplications or code) include machine instructions for a programmableprocessor, and can be implemented in a high-level procedural and/orobject-oriented programming language, and/or in assembly/machinelanguage. As used herein, the terms machine-readable medium andcomputer-readable medium refer to a computer program product, apparatusand/or device (e.g., magnetic discs, optical disks, memory, ProgrammableLogic Devices (PLDs)) used to provide machine instructions and/or datato a programmable processor, including a machine-readable medium thatreceives machine instructions.

To provide for interaction with a user, the systems and techniquesdescribed here can be implemented on a computer having a display device(e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor)for displaying data to the user and a keyboard and a pointing device(e.g., a mouse or a trackball) by which the user can provide input tothe computer. Other kinds of devices can be used to provide forinteraction with a user as well; for example, feedback provided to theuser can be a form of sensory feedback (e.g., visual feedback, auditoryfeedback, or tactile feedback); and input from the user can be receivedin a form, including acoustic, speech, or tactile input.

The systems and techniques described here can be implemented in acomputing system that includes a back end component (e.g., as a dataserver), or that includes a middleware component (e.g., an applicationserver), or that includes a front end component (e.g., a client computerhaving a user interface or a Web browser through which a user caninteract with an implementation of the systems and techniques describedhere), or a combination of such back end, middleware, or front endcomponents. The components of the system can be interconnected by a formor medium of digital data communication (e.g., a communication network).Examples of communication networks include a local area network (LAN), awide area network (WAN), and the Internet.

The computing system can include clients and servers. A client andserver are generally remote from each other and typically interactthrough a communication network. The relationship of client and serverarises by virtue of computer programs running on the respectivecomputers and having a client-server relationship to each other.

In some implementations, the engines described herein can be separated,combined or incorporated into a single or combined engine. The enginesdepicted in the figures are not intended to limit the systems describedhere to the software architectures shown in the figures.

1-47. (canceled)
 48. An apparatus comprising: a reaction chamberincluding one or more pairs of electrodes configured to generate aseries of electric arcs to synthesize a reactant gas containing at leastnitrogen and oxygen to a product gas containing nitric oxide; a sensorconfigured to measure one or more characteristics of the reactant gas orthe product gas; and a controller in communication with the one or morepairs of electrodes and the sensor, the controller being configured todetect a triggering event based on the one or more characteristics ofthe reactant gas or the product gas and initiate the series of electricarcs a predetermined amount of time ahead of the triggering event toincrease a concentration of nitric oxide in the product gas.
 49. Theapparatus of claim 48, wherein the predetermined amount of time ahead ofthe triggering event is configured to be adjusted to control theconcentration of nitric oxide in the product gas.
 50. The apparatus ofclaim 48, wherein the one or more characteristics include at least oneof a direction of flow of the reactant gas, a tidal volume of a flow ofthe reactant gas, a timing of a flow of the reactant gas, a change intemperature of a flow of the reactant gas, a change in pressure of the aof the reactant gas, and a flow rate of the reactant gas.
 51. Theapparatus of claim 48, wherein the one or more characteristics includeat least one of timing and volume of an inspiration.
 52. The apparatusof claim 51, wherein the predetermined amount of time ahead of thetriggering event is adjusted based on the at least one of timing andvolume of the inspiration.
 53. The apparatus of claim 48, wherein thecontroller is configured to track at least one of timing and volume of aprevious inspiration and predict at least one of timing and volume of asubsequent inspiration.
 54. The apparatus of claim 53, wherein thecontroller is configured to adjust the predetermined amount of timeahead of the triggering event based on the at least one of timing andvolume of the subsequent inspiration.
 55. An apparatus comprising: areaction chamber including one or more pairs of electrodes configured togenerate a series of electric arcs to synthesize a reactant gascontaining at least nitrogen and oxygen to a product gas containingnitric oxide, the reaction chamber being at least partially positionedwithin a tube into which the product gas is delivered; a sensorconfigured to measure one or more characteristics of a flow of a gas inthe tube, wherein the one or more characteristics include at least oneof volume and timing of inspiration; and a controller in communicationwith the one or more pairs of electrodes and the sensor, the controllerbeing configured to detect a triggering event based on the at least oneof volume and timing of inspiration and initiate the series of electricarcs a predetermined amount of time ahead of the triggering event toincrease a concentration of nitric oxide in the product gas.
 56. Theapparatus of claim 55, wherein the predetermined amount of time ahead ofthe triggering event is configured to be adjusted to control theconcentration of nitric oxide in the product gas.
 57. The apparatus ofclaim 55, wherein the one or more characteristics further include atleast one of a direction of the flow of the gas, a tidal volume of theflow of the gas, a timing of the flow of the gas, a change intemperature of the flow of the gas, a change in pressure of the flow ofthe gas, and a flow rate of the flow of gas.
 58. The apparatus of claim55, wherein the tube comprises one of a tracheostomy tube, anendotracheal tube, a nasal tube, a ventilator tube, and an inspiratoryline.
 59. The apparatus of claim 55, wherein the predetermined amount oftime ahead of the triggering event is adjusted based on the at least oneof timing and volume of inspiration.
 60. The apparatus of claim 55,wherein the controller is configured to track at least one of timing andvolume of a previous inspiration and predict at least one of timing andvolume of a subsequent inspiration.
 61. The apparatus of claim 60,wherein the controller is configured to adjust the predetermined amountof time ahead of the triggering event based on the at least one oftiming and volume of the subsequent inspiration.
 62. A method forgenerating nitric oxide comprising: measuring one or morecharacteristics of at least one of a flow of reactant gas into areaction chamber and a flow of product gas out of the reaction chamber;detecting a triggering event based on the one or more characteristics;initiating a series of electric arcs in the reaction chamber apredetermined amount of time ahead of the triggering event to synthesizea reactant gas containing nitrogen and oxygen to a product gascontaining nitric oxide; and adjusting the predetermined amount of timeahead of the triggering event to control a concentration of nitric oxidein the product gas.
 63. The method of claim 62, wherein the one or morecharacteristics further include at least one of a direction of the flowof the reactant gas or the flow of product gas, a tidal volume of theflow of the flow of the reactant gas or the flow of product gas, atiming of the flow of the reactant gas or the flow of product gas, achange in temperature of the flow of the reactant gas or the flow ofproduct gas, a change in pressure of the flow of the reactant gas or theflow of product gas, and a flow rate of the flow of the reactant gas orthe flow of product gas.
 64. The method of claim 62, wherein the one ormore characteristics include at least one of timing and volume of aninspiration.
 65. The method of claim 64, further comprising adjustingthe predetermined amount of time ahead of the triggering event based onthe at least one of timing and volume of inspiration.
 66. The method ofclaim 62, further comprising tracking at least one of timing and volumeof a previous inspiration and predict at least one of timing and volumeof a subsequent inspiration.
 67. The method of claim 66, furthercomprising adjusting the predetermined amount of time ahead of thetriggering event based on the at least one of timing and volume of thesubsequent inspiration.